OVERALL: PROJECT SUMMARY The Yale SPORE in Skin Cancer (YSPORE), now in its second funding cycle, involves a broad range of projects and investigators with diverse expertise, whose goal is to decrease mortality from melanoma by developing methods to prevent the disease and treat patients once it metastasizes. YSPORE leans on the immense scientific and clinical strengths at Yale School of Medicine and Yale Cancer Center including immunobiology, genetics, epigenetics, quantitative sciences, immuno-oncology, nanoparticles, animal models, and digital pathology. YSPORE investigators have made major contributions in recent years to understanding the effects of ultraviolet damage on melanocytes, determining the molecular events that lead to melanoma progression and developing novel immune therapy approaches for melanoma patients with advanced disease. Recent advances in systemic therapies for advanced melanoma, particularly immune checkpoint inhibitors, that prolong survival, pose a new set of challenges for clinicians which will be addressed by the proposed research program. The YSPORE translational research team proposes to accomplish the objective of decreasing morbidity and mortality from skin cancer through five specific aims: Specific Aim 1: Develop novel bioadhesive sunscreens and triplet-state quenchers for prevention of melanoma and test them in pilot clinical trials; Specific Aim 2: Develop liquid biopsy approaches for melanomas that metastasize to sites that are difficult to biopsy. Liquid biopsies will then be studied in patients treated with PD-1 inhibitors to identify predictors of response and determine mechanisms of resistance; Specific Aim 3: Study novel drugs that target the epigenetic modifier KDM5, to enhance T cell infiltration in tumors that are unresponsive to immune checkpoint inhibitors; Specific Aim 4: Develop new approaches to overcoming resistance to PD-1 inhibitors by co-targeting the innate and adaptive immune systems; and Specific Aim 5: Develop new research directions to decrease mortality from melanoma and nurture the next generation of translational investigators focusing on skin cancer through a Developmental Research Program and a Career Enhancement Program. We propose three cores (Administrative Core, Biospecimen Core and Biostatistics and Bioinformatics Core) to support the projects, their clinical aims, mechanistic studies, and biomarker development for clinical application. The Projects and Cores are designed to be highly coordinated with the goal of maximizing resources and potential impact. New collaborations will be established during the funding period through the Developmental Research Program with the support of the Administrative Core. Collaborations with other institutions and skin cancer SPORE sites will be fostered by the Administrative Core. These coordinated efforts will enhance analysis of patient samples, use of cell cultures and animal models, and development of predictive biomarker assays. Our purpose is to translate the innovative approaches proposed here to clinical therapies for prevention and treatment of skin cancer.